Halo-derivatives of 4-hydroxy-17alpha-methyl-testosterone



but)

wherein Y=H, u-Cl, or B-Cl R==H or Ac where Ac=acyl group derived froman acid containing not more than 9 carbon atoms,

and to processes for preparing them.

B. Camerino et al. have disclosed (in I. Am. Chem. Soc. 78, 1956, page3540), a number of steroids of the androstane series (having either achlorine or a hydroxy group in 4-position), which possess outstandinganabolic activity and low androgenic effect. Moreover, all of the3,058,248 Patented Dec. ii, 19%2 52 products described in thepublication are highly active when administered subcutaneously.

More recently, B. Camerino et al. have described (in British patentspecification 848,288) 4-hydroxy-17u-methyl-testosterone, which has ahigh anabolic activity and low androgenic efiect even when administeredorally. Orally active anabolic substances are especially sought after inthe clinic.

The new products of the invention possess oral anabolic activity and arevaluable as intermediates for the manufacture of 1,2-dehydro-,6,7-dehydroand 1,226,7- dehydro-derivatives of4-hydroxy-17a-methyl-testosterone, which are new oral anabolicsubstances disclosed and claimed in our above-mentioned copendingapplication.

In particular, our invention provides the following new compounds:

2a-bromo-4-hydroxy-17a-methyl-testosterone, 2oc-bromo-4-hydroxyl7a-methyl-testosterone-4-acetate,6a-chloro-4-hydroxyi7a-methyl-testosterone,6u-chloro-4-hydroxy-17a-methyl-testosterone-4-acetate,6/3-chloro-4-hydroxy-17ot-methyl-testosterone,6fi-chloro-4-hydroxy-17a-methyl-testosterone-4-acetate,2zx-bromo-6zx-chloro-4-hydroxy-17a-methyl-testosterone,2a-brorno-6B-chloro-4-hydroxyl 7a-methyl-testosterone,2a-bromo-6fi-chloro-4-hydroxy-17u-methyl-test0sterone- 4-acetate It isto be understood that other 4-acyloxy products having the aforesaidstructural formula are included within the scope of the presentinvention. The 4-esters can be derived from aliphatic or cycloaliphaticor aromatic acids containing not more than 9 carbon atoms, such as, forexample, formate, acetate, propionate, butyr- OH ca, ChlorinationBrommatlon (in acetic acid) (both in halogcnated 501- \J vents and in OR Cl acetic acid) (IV: R=ED (IVa: R A 0) O z 0 H OH A0113 1""CH3 OR C1R=H) l (Va. R.=Ac) Chlorination Bromination t in acetic acid) (both inhalo- Chlorination genated solvents and in (in halogenated OH O R aceticacid) 0 R solvents) CH3 R=H) It; R=H) (Ia: R=Ac) (Iia: R=Ac) O H om Brj0:

7 l Chlorination Bromination O R 01 (VI: R=H) (in halogenated (both inhalo- (VIar R=Ac) solvents) genated solvents and in O R 01 acetic acid)(III: R=H) (Ilia: R=Ac) ate, valerate, succinate, heptancate,cyclopentyl-propionate, cyclohexane acetate, hexahydrobenzoate,benzoate, phenylpropionate and analogues.

The products of our invention are prepared from 4- hydroxy (or 4acyloXy-)17a-methyl-testosterone described by B. Camerino et al. in theBritish patent specification 848,288.

The synthesis of the products of the invention is carried outsubstantially in accordance with the preceding schematic illustration.

In general terms, the process of our invention comprises halogenating4-hydroXy-(or 4-acyloxy-)l7ot-methyl-testosterone (I and la), eitherwith bromine in the 2- position or with chlorine in 6-position. Bydehydrohalogenation of the obtained halo-steroids, products whichcontain respectively a double bond in the 1,2-position or in the6,7-position or two double bonds in the 1,2- and 6,7- position may beproduced. Esterification of the 4-hydroxy group or hydrolysis of the4-acyloXy group may be carried out between any steps in the synthesis.

4-hydroXy-(or 4-acyloxy-) l7a-methyl-testosterones (I and la) may bebrominated in the 2-position either with bromine or withN-bromo-succinimide in an organic halogenated solvent such as carbontetrachloride, chloroform or methylene dichloride or in acetic acid, toproduce 20:- bromo-4-hydroxy-(or 4-acyloxy-) 17 oc-methyl-testoSteroncS(II or Ila); or may be chlorinated in the 6-position either withchlorine or with N-chloro-succinimide in an organic halogenated solventsuch as carbon tetrachloride, chloroform or methylene dichloride toyield 6B-chloro4-hydroXy-(or 4-acyloXy-)17ot-mcthyl-testosterones (H1 orIila); or chlorinated with chlorine in acetic acid to yield the6ot-chloro-4-hydroxy-(or 4-acyloxy-)17a-methyl-tes tosterones (IV orIVa).

By bromination in the 2-position of the GB-chloro-steroid (III or Ilia)and of 6ot-chloro-steroid (IV or IVa) respectively, the2a-bromo6B-chloro-steroid (VI or VIa) and the2ix-bromo-6u-chloro-steroid (V or Va) are respectively obtained.

The 2ot-bromo-steroid (II or Ila) by chlorination in an organichalogenated solvent such as carbon tetrachloride, chloroform ormethylene dichloride gives the Zea-bromo- 6fl-chloro-steroid (VI or Via)and by chlorination in acetic acid gives the ZCv-bIOmO-oa-ChlOIO-St6f0id(V or Va).

We have stated the steric configuration of the 2-bromoand6-chloro-derivatives upon following considerations. It is known (L. F.Fieser and M. Fieser, Steroids, Reinhold Publishing Corporation, NewYork, 1959, page 280), that the bromination of 3-ket0-5oc-ster0idsalfords the 2ozbromo-derivativ e having the halogen-atom equatorial. TheZfi-brorno-derivative has the halogen-atom aXiaLinvolving a remarkabledestabilization due to the electrical repulsion between the C-O and CBrdipoles. Therefore, should such a compound result, it would be so labilethat it should escape isolation. Indeed all our attempts to get theZfl-bromo-derivative were unsuccessful.

On the contrary, the chlorination of 4-hydroXy-17emethyl-testosteronemay lead to two different stereoisomers -chloro-derivatives, accordingto the manner in which said chlorination is performed.

In. other words, the chlorination of 4-hydroxy-17otmethyl-testosteronecarried out with chlorine or with l i-chloro-succinimide in an organichalogenated solvent affords a o-chloro-derivative having melting point156- 159 C., and

A5323? at 282 m while the chlorination in acetic acid yields a6-chloroderivative having a melting point 189-493 C.,

It is known (H. J. Ringold et al., Experientia 17, 1961, 65 that among3-keto-6-chloro-A -steroids, the 6,8-chloro-derivative shows and U.V.max-absorption at a wave length higher than the fia-chloroderivative. Wemay,

therefore, conclude that chlorination of4-hydroxy-17otmethyl-testosterone in halogenated solvents yields the 68- isomer, while chlorination in acetic acid yields the 6misomer.

The hromination of 6,8-chloro-4-hydroxy-Not-methyltestosterone yields aproduct melting at 173182 C. Since the 2-bromo-atom always assumes the2a-configuration according to the above-mentioned considerations, theproduct obtained is the 2ot-bromo-6fl-chloro-4hydroxy-17ot-methyhtestosterone. The bromination of 6OL-ChlOIO-4-hydroxy-17tt-methyl-testosterone as well as the chlorination in aceticacid of 2ot-bromo-4-hydroxy-Not-methyltestosterone yields a productmelting at 175-185" C., which is different from the above-mentioned one,even if by dehydrohalogenation of both isomeric compounds the sameproduct, i.e. 1,2,I6,7-d6hYdlO-4-hYdIOXY-1706-Hlethyl-testosterone isobtained. In fact, this product is the 20:-bromo-6a-chloro-4-hydroxy-17ot-methyl-testosterone.

As it was above already pointed out, the stable equatorial configurationa must be ascribed to the bromo-atom in the 2-position, the two isomeric2-bromo-6-chloroderivatives diiiering only in the configuration of thechloro-atom in the 6-position.

This is confirmed by the comparison of the I.R.-spectra characteristicof the 2 isomers. The 6-chloro-derivative obtained by chlorination inacetic acid of 2a-bromo-4- hydroxy-17a-methyl-testosterone presents, inthe I.R.-spectram, a band at 3570 cm.- due to the hydroXy-group in thel7/3-position; and, besides, a hydroxy group at 3320 cmf in this casethe hydroxy group forms a strong intramolecular hydrogen-bond (seeBellamy, The Infrared Spectra of Complex Molecules, John Wiley and Sons,Inc., New York, 8, page 95). On consideration of the steric models, wecan easily realize that said hydrogen-bond may be formed only if thechloro-atom in the 6-position has the tit-configuration.

The 6-chloro-derivative obtained by chlorination in halogenated solventsof 2u-bromo-4-hydroxy-17a-methyltestosterone presents, in theI.R.-spectrum, a band at besides, a hydroXy-group-band at 3480 cmr genbond weaker than that of the previous case. On the consideration of thesteric models, we can easily realize said hydrogen-bond may be formedwhen the chloro-atom in the 6-position has the 6,8-configuration.

1,2 dehydro 4 hydroxy-(or 4-acy1oxy-)17a-methyltestosterones may beobtained from the 2-bromo-derivatives (II and Ila) by dehydrobrominationwith lithium bromide and lithium carbonate in dimethylforrnamide under anitrogen atmosphere at about 80-110 C. for 1030 hours.

6,7 dehydro 4 hydroXy-(or 4-acyloXy-)17a-methyltestosterones areprepared analogously either from the fi-chloroor from theGOL-CiJIOI'O-dCIlVEifiVeS (III, 1116:, EV, IVa) by dehydrochlorinationwith lithium chloride and lithium carbonate in dimethylformamide.

1,2 6,7-dehydro-4-hydroxy- (or 4-acyloxy) 17 ot-methyh testosterone maybe prepared from the corresponding 2abrorno-6a-chloroor2a-bromo-6fl-chlcroderivatives (V or Va and VI or VIa) bydehydrohalogenation with lithium chloride, lithium bromide and lithiumcarbonate in the presence of dime-thyl-form-amide.

The acylation in the 4-position of the new compounds of the presentinvention may be carried out with the chloride or the anhydride of anorganic acid having not more than 9 carbon atoms optionally in thepresence of tertiary amines such as pyridine, between any steps of the:

synthesis. The hydrolysis of the acyloxy group in the 4-po-sition of thenew compounds having the aforesaid general structural formula may beeffected between any steps of the synthesis with alkali according toknown procedures.

The compounds of the invention show unexpected ana-- bolic activity andare particularly useful when orally administered.

The invention is illustrated, but not limited, by the followingpreferred embodiments:

Example 1 Zea-BROMO-4-HYDROXY-l7a-METHYL-TESTOSTERONE (11) FROM (I)PROCESS WITH BROIWIINE 3 g. of 4-hydroxy-17a-rnethyl-testosterone (I)are dissolved in 30 cc. of anhydrous chloroform; the solution is cooledto C., and 1.44 g. of bromine, dissolved in cc. of anhydrous chloroform,are added under stirring. A quick absorption of bromine is observed. Thechloroform solution is washed with water, 5% aqueous sodium bicarbonate,then with water to neutrality, dried over anhydrous sodium sulphate andevaporated to dryness under vacuum at a temperature under 35 C. Theresidue is crystallized twice from aqueous methanol.

1.6 g. of (II), melting at 102104 C. with dec0mposition, are obtained.

ethanol Hnax.

at 286 m (e=10,750)

Example 2 2a. BROMO-4-HYDROXY-1'TmME'I'HYL TESTOSTERONE (II) FROM (I)PROCESS WITH N-BROMOSUCCIN- IMIDE 1.59 g. of4-hydroxy-17et-methy1-testosterone (I) are reacted with 0.89 g. ofN-bromo-succinimide in boiling 35 cc. CCL; for minutes and under directillumination. The mixture is cooled, filtered, and the filtrate isevaporated to dryness under vacuum at a temperature below C. The residueis crystallized from aqueous methanol. The product melts at 102-105" C.,has an absorption maximum at 286 mp. and is identical with the product(II) obtained as described in Example 1.

Example 3 2a BROMO 4: HYDROXY 17a METHYL TESTOS- TERONE-4-ACETATE (IIa:AczCOCHa) FROM (II) 1 g. of product (II), dissolved in 8 g. of pyridineis acetylated in known manner with 1 g. of acetic anhydride at roomtemperature. The product (Ila) melting at 80 C. (recrystallized fromether/petroleum ether) is obtained.

ethanol mer.

at 251 my. (6 14,000)

Example 4 1,2-DEHYDRO-4-HYDROXY-17a-METHYL-TESTOSTERONE FROM (II) ews!at 305 mp, =5,l00)

M213? at 244. m (e=7,400), [a]% =+6 li2 (c.=1% in chloroform) Example 56B CHLORO 4 HYDROXY 17a. METHYL TESTOS- TERONE (III) FROM (I) PROCESSWITH CHLORINE IN CHLOROFORM To a solution of 2 g. of4-hydroxy-17a-methyl-testosterone (I) in 10 cc. of anhydrous chloroform,0.45 g. of chlorine dissolved in 3.4 cc. of anhydrous chloroform areadded. The chloroform solution is washed with 6 water, aqueous 5% sodiumbicarbonate and with water to neutrality, dried over anhydrous sodiumsulphate and evaporated to dryness under vacuum at a temperature under35 C. The residue is treated with ether, the product is filtered andcrystallized from ether. 0.75 g. of (III) melting at 156-159 C. areobtained.

A323? at 282 m (e=11,300), [a] 3=7:l;2 (o.=1% in chloroform) Example 6 63 CHLORO 4 HYDROXY 17a METHYL TESTOS- TERONE (III) FROM (I) PROCESS WITHN-CHLORO- SUCCINIMIDE IN CHLOROFORM 1.59 g. of4-hydroxy-l7a-methyl-testosterone (I) are reacted with 0.67 g. ofN-chlorosuccinimide in 35 cc. of boiling chloroform for 30 minutes andunder direct illumination. The mixture is cooled, filtered and thefiltrate is evaporated to dryness at a temperature below 35 C. Theresidue is crystallized from ether, the product (III), identical withthat yielded as described in Example 5, is obtained.

Example 7 613 CHLORO at HYDROXY 17a. METHYL TESTOS- TERONE-4-ACETATE(IIIa:Ac:COCHa) FROM (III) ethnnol at 245 my (e=1l,700)

Example 8 6a CHLORO 4 HYDROXY 17a. METHYL TESTOS- TERONE (IV) FROM (I)PROCESS WITH CHLORINE IN ACETIC ACID To a stirred solution of 2 g. of4-hydroxy-l7a-methyltestosterone (I) in 10 cc. of glacial acetic acid,0.45 g. of chlorine dissolved in 3.5 cc. of chloroform are added bycooling to +5 C.

The solution is washed with water, aqueous 5% sodium bicarbonate andwith water to neutrality, dried over anhydrous sodium sulphate andevaporated under vacuum at a temperature not above 35 C. The residue istreated with ether, the product (IV) is filtered and crystallized fromether. Melting point: 189-193" C.

By acetylation of (IV) with acetic anhydride in pyri dine, the 4-acetate(IVa) melting at l83186 C. is obtained.

Example 9 6,7-DEHYDRO 4-HYDROXY-17a-METHYL-TESTERONE FROM (IV) 1.1 g. of6a-chloro-4-hydroxy-17a-methy1-testosterone (IV) dissolved in 26 cc. ofdimethylformamide are reacted with 1.70 g. of lithium chloride and 1.20g. of lithium carbonate under nitrogen with stirring at C. for 20 hours.The solution is cooled and poured into 200 cc. of water. The steroid isextracted with ethyl acetate, the extract is washed with water toneutrality, dried over anhydrous sodium sulphate, decolorized withactive carbon and concentrated to small volume. The residual solution isfiltered, treated with ether and the product is filtered, washed withether and crystallized twice from ethyl acetate.

at 319 m $21,500); M.P.=209-211 0.

Example 10 6,'T-DEIIYDRO-4HYDROXY-17a-METHYL-TESTOSTERONE FROM (III) 1.1g. of 6/3-chloro-4-hydroxy-l7ot-methyl-testosterone (III) dissolved in26 cc. of dimethylformamide are reacted with 1.70 g. of lithium chlorideand 1.20 g. of lithium carbonate under nitrogen with stirring at 105 C.for 20 hours. The solution is cooled and poured into 200 cc. of water.The steroid is extracted with ethyl acetate, the extract is washed withwater to neutrality, dried over anhydrous sodium sulphate, decolorizedwith active carbon and concentrated to small volume. The residualsolution is filtered, treated with ether and the product is filtered,washed with ether and crystallized .twice from ethyl actate. M.P.=209211C.

x333 at 319 Inn Example 11 Za-BROMO-65-CHLOR0-4-HYDROXY-17a-METHYL-TESTOSTERONE (VI) FROM (11) 1.20 g. of2ot-bromo-4-hydroxy-l7a-methyl-testosterethanol Wnnx.

one (II) dissolved in 7.5 cc. of anhydrous chloroform are reacted with212 mg. of chlorine dissolved in 2.1 cc. of anhydrous chloroform at 5 C.with stirring. A quick absorption of chlorine is observed. Thechloroform solution is washed with water, aqueous 5% sodium bicarbonateand finally with water to neutrality. The extract is dried overanhydrous sodium sulphate and evaporated to dryness under vacuum at atemperature under 35 C. 'The residue is crystallized twice from ether.

2a-BROMO-6B-CHLORO-4-HYDROXYJTat-METHYL- TESTOSTERONE (VI) FROM (III)2.07 g. of 6,8-chloro-4-hydroxy-l7a-rnethyl-testosterone (III) dissolvedin 15 cc. of anhydrous chloroform are reacted with 0.95 g. of brominedissolved in cc. of anhydrous chloroform at 5 C. with stirring. A quickabsorption of bromine is observed. The chloroformic solution is washedwith water, aqueous 5% sodium bicarbonate and finally with water toneutrality. The extract is dried over anhydrous sodium sulphate andevaporated to dryness under vacuum at a temperature under 35 C. Theresidue is treated with ether; the raw product (VI) melting at 155-165C. with decomposition is obtained. By crystallization from ether, theMP. rises up to 173-182 C. with decomposition. IR. absorption bands at3570 cm." and at 3480 cm.

Example 13 2a-BROMO-6a-CHLORO-l-HYDROXY-l7a-METHYL- TESTOSTERONE (V)FROM (IV) By bromination of IV in the same conditions as of Example 12the 2e-bromo-6ot-chloro-4-hydroxy-17amethyl-testosterone melting at175-185 C. is obtained. LR. absorption bands at 3570 cm.- and at 3320cm.

Example 14 2a-BROMO-6aCHLORO-4-HYDROXY-17ct-METHYL- TESTOSTERONE (V)FROM (II) By chlorination of II in acetic acid under the same conditionsas in Example 8, the2a-bromo-6a-chloro-4-hydroxy-l7u-methyl-testosterone melting at 175-185C. is obtained. LR. absorption bands at 3570 cm. and at 3320 cm.-

Example 15 1,2 :6,7-DEHYDRO-4-HYDROXY-17a-METHYL-TESTOS- TERONE FROM (V)OR FROM (VI) 2 g. of 2a-bromo-6B-chloro-4-hydroxy-17a-methyltestosterone(VI) or 2ot-broIno-6ot-chloro-4-hydroxy-170; methyl-testosterone (V)dissolved in 30 cc. of anhydrous dimethyl-formamide are reacted with2.25 g. of lithium chloride, 2.25 g. of lithium bromide and 3.2 g. oflithium carbonate at C. for 20 hours in a nitrogen atmos phere and understirring. The solution is cooled and poured into 200 cc. of water; thesteroid is extracted with ethyl acetate and the extract is Washed withwater, dried over anhydrous sodium sulphate and evaporated to dry= mess.The residue is crystallized many times from ether, and decolorized withactive carbon. The product melt ing at ISO-483 C. is obtained.

at 232 my. (e=l1,800) at 348 H1/.l(=8,400)

mux.

ethenol max.

Example 16 2a BROMO 4 HYDROXY 17a METHYL TESTOS= TERONE (II) FROM (I)BROMINATION IN ACETIC ACID 0.63 g. of bromine dissolved in 7.15 cc. ofanhydrous acetic acid, are added, at 5 C. and under stirring to asolution of 1.25 g. of 4-hydroxy-l7a-methyl-testosterone (I) in 7 cc. ofanhydrous acetic acid. The solution is poured into 70 cc. of water andthe steroid is extracted with ether. The organic extract is washed withwater, aqueous 5% sodium bicarbonate, and with water to neutrality,dried over anhydrous sodium sulphate and concentrated to small volume.The product (II), identical with that prepared as described in Examples1 and 2, is obtained.

Example 1 7 2a-BROMO-4-HYDROXY-17a-METHYL-TESTOSTERONE (II) FROM(IIaZAczC'OCHs) A mixture of 0.5 g. of 2a-brorno-4-hydroxy-17a-methy1-testosterone-4-acetate (Ila: Ac=COCH dissolved in 15 cc. of methanol and0.5 g. of potassium bicarbonate dissolved in 5 cc. of water, is allowedto react at room temperature for 18 hours. The solution is neutralizedwith acetic acid, poured into water, and the steroid is extracted withether. The extract is washed with water to neutrality, dried overanhydrous sodium sulphate and evaporated to dryness at a lowtemperature. The residue is crystallized from ether. The product (II),identical with that obtained as described in Examples 1, 2, and 19, isobtained.

Pharmacological activity.The anabolic and androgenic activities of anumber of products of the present invention are hereinafter reported incomparison with those of 17a-rnethy1-testosterone and4-hydroxy-l7a-methyltestosterone. The anabolic (myotropic) andandrogenic properties have been determined in male castrated ratsweighing 3040 g., according to the method of Hershberg et al. (Proc.Soc. Exp. Biol. and Med. 83, 1953, page The increase in weight oflevator ani muscle has been considered as an expression of anabolicactivity, while the increase in weight of prostate gland has beenconsidered as an expression of androgenic activity. The reported data inthe following Table I are referred to Wet weights of the organs.

For comparing the anabolic and androgenic activities of the testedsteroids the following ratio was established:

=therapuetio index (T.I.) The steroids were administered orally.

TABLE 1.-ANABOLlC AND ANDROGENIC ACTIVITIES (ORAL ADMINISTMTEON) DosesLevator Steroid (mgJ ani, mg. Prostate T.I

day)

Castrated controls 8. 6 9. 3 17a-methyl-testosterone 1 13. 4 33. 7 0. 18D a- 2 17.7 43. 9 0. 26 4 25. 5 73. 7 0. 2B 0. 5 22. 6 32. 4 0.61 1 22.8 30. 7 0. 66 D0.' 2 30. 7 48.1 0. 57 2a-bromo-4-hydroxy-l7a-n1ethyltestosterone (II) 0.5 19.2 22.0 0.831,2-dehydro-4-hydroXy-17a1nethyltestosterone 0. 14. 8 19.2 0. 63 0. 524. 7 21. 3 1. 34 y testosterone (III) t 0.25 19. 5 19. 9 1. 02 Do 0. 52L 6 24. 8 0. 83 Do 1 25. 3 34. 0 0. 68 6fl-chloro-4-hydroxy-17a-inethy1- testosterone--acetate (III Ac=OOCH 0.5 17.6 21.8 0.72 Do 121. 9 26. 4 0. 77

TABLE 2.RELATIVE ANABOLIC POTENCIES Relative Steroid anabolic potency17a-rnethyl-testosterone 1 4-hydroxy-lm-moLhyl-testosterone 3 CompoundII 4. 6 Compound IV i i 5.7 Compound IVa (Ao=COCH3) 4 We claim:

1. A derivative of 4-hyClIOXy-170t-1'I16ll1Y1-t6SlOStCIOI1C taken fromthe group consisting of those having one of the following formulae:

in which is taken from the group consisting of H and Ac, the Ac radicalbeing an acyl radical of the formula R CO in which R is a hydrocarbonradical having not more than nine carbon atoms.

2. 2a-bromo-4-hydroXy-l7ot-rnethyl-testosterone.

3. 2rx-bromo-4-hydroxy 17a methyl testosterone-4- acetate.

4. 6a-chloro-4-hydroxy-l7a-methyl-testosterone.

5. 6a-ohloro-4hydroxy 171x methyl testosterone-4- acetate.

6. 6[-3-chloro-4-hydroxy-17a-n1ethyl-testosterone.

7. 6fi-chloro-4-hydroxy i methyl testosterone-4- acetate.

8. Zea-brOmO-Go:-Chl010-4-hYdrOXy 17m methyl-testosterone.

9. 2a-bromo-6B-chloro-4-hydroxy 171x methyl-testosterone.

10. A process of preparing a compound of the group consisting of6m-chloro-4-hydroXy-(and 4-acyloXy-)-17amethyl-testosterone of6a-chloro-4-hydroxy-(and 4-acyl- OXY)2oc-br0rn0 17a methyl testosterone,comprising chlorinating a compound of the group consisting of4-hydroXy-(and 4-acyloxy)-l7a-methyl-testosterone and of 4-hydroxy- (and4-acyloxy-) -Za-b10n'10- 17 a-niethyl-testos terone, the acyl radicalbeing of the formula R-CO in which R is a hydrocarbon radical having upto nine carbon atoms, said chlorinating being carried out by reactingwith chlorine in the presence of acetic acid.

OTHER REFERENCES Ringold et al.: J.A.C.S. 81, page 34-85 (1959).

1. A DERIVATIVE OF 4-HYDROXY-17A-METHYL-TESTOSTERONE TAKEN FROM THEGROUP CONSISTING OF THOSE HAVING ONE OF THE FOLLOWING FORMULAE: